Cytarabine is the backbone of AML therapy, but the dose used during induction has remained controversial. Using an intermediate dose of cytarabine, compared with conventional dose, was shown to ...improve disease-free and overall survival in adult patients in China up to age 55, particularly in patients with intermediate cytogenetic risk.
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Ferritins: furnishing proteins with iron Bradley, Justin M.; Le Brun, Nick E.; Moore, Geoffrey R.
JBIC. Journal of biological inorganic chemistry/JBIC, Journal of biological and inorganic chemistry,
03/2016, Letnik:
21, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Ferritins are a superfamily of iron oxidation, storage and mineralization proteins found throughout the animal, plant, and microbial kingdoms. The majority of ferritins consist of 24 subunits that ...individually fold into 4-α-helix bundles and assemble in a highly symmetric manner to form an approximately spherical protein coat around a central cavity into which an iron-containing mineral can be formed. Channels through the coat at inter-subunit contact points facilitate passage of iron ions to and from the central cavity, and intrasubunit catalytic sites, called ferroxidase centers, drive Fe
2+
oxidation and O
2
reduction. Though the different members of the superfamily share a common structure, there is often little amino acid sequence identity between them. Even where there is a high degree of sequence identity between two ferritins there can be major differences in how the proteins handle iron. In this review we describe some of the important structural features of ferritins and their mineralized iron cores, consider how iron might be released from ferritins, and examine in detail how three selected ferritins oxidise Fe
2+
to explore the mechanistic variations that exist amongst ferritins. We suggest that the mechanistic differences reflect differing evolutionary pressures on amino acid sequences, and that these differing pressures are a consequence of different primary functions for different ferritins.
Abstract
BACKGROUND
Middle meningeal artery (MMA) embolization has emerged as a promising treatment for chronic subdural hematoma (cSDH).
OBJECTIVE
To determine the safety and efficacy of MMA ...embolization.
METHODS
Consecutive patients who underwent MMA embolization for cSDH (primary treatment or recurrence after conventional surgery) at 15 centers were included. Clinical details and follow-up were collected prospectively. Primary clinical and radiographic outcomes were the proportion of patients requiring additional surgical treatment within 90 d after index treatment and proportion with > 50% cSDH thickness reduction on follow-up computed tomography imaging within 90 d. National Institute of Health Stroke Scale and modified Rankin Scale were also clinical outcomes.
RESULTS
A total of 138 patients were included (mean age: 69.8, 29% female). A total of 15 patients underwent bilateral interventions for 154 total embolizations (66.7% primary treatment). At presentation, 30.4% and 23.9% of patients were on antiplatelet and anticoagulation therapy, respectively. Median admission cSDH thickness was 14 mm. A total of 46.1% of embolizations were performed under general anesthesia, and 97.4% of procedures were successfully completed. A total of 70.2% of embolizations used particles, and 25.3% used liquid embolics with no significant outcome difference between embolization materials (P > .05). On last follow-up (mean 94.9 d), median cSDH thickness was 4 mm (71% median thickness reduction). A total of 70.8% of patients had >50% improvement on imaging (31.9% improved clinically), and 9 patients (6.5%) required further cSDH treatment. There were 16 complications with 9 (6.5%) because of continued hematoma expansion. Mortality rate was 4.4%, mostly unrelated to the index procedure but because of underlying comorbidities.
CONCLUSION
MMA embolization may provide a safe and efficacious minimally invasive alternative to conventional surgical techniques.
Graphical Abstract
Graphical Abstract
The proteins responsible for controlling electron transfer in bacterial secondary metabolism are not always known or characterised. Here we demonstrate that many bacteria contain a set of unfamiliar ...ferredoxin encoding genes which are associated with those of cytochrome P450 (CYP) monooxygenases and as such are involved in anabolic and catabolic metabolism. The model organism
M contains eleven of these genes which encode 3Fe-4S or 4Fe-4S single cluster containing ferredoxins but which have unusual iron-sulfur cluster binding motif sequences,
XX
XX
(X)
P, where '
' indicates a variable amino acid residue. Rather than a cysteine residue, which is highly conserved in 4Fe-4S clusters, or alanine or glycine residues, which are common in 3Fe-4S ferredoxins, these genes encode at this position histidine, asparagine, tyrosine, serine, threonine or phenylalanine. We have purified, characterised and reconstituted the activity of several of these CYP/electron transfer partner systems and show that all those examined contain a 3Fe-4S cluster. Furthermore, the ferredoxin used and the identity of the variable motif residue in these proteins affects the functionality of the monooxygenase system and has a significant influence on the redox properties of the ferredoxins. Similar ferredoxin encoding genes were identified across
species, including in the pathogenic
and
, as well as in a wide range of other bacteria such as
and
. In the majority of instances these are associated with CYP genes. These ferredoxin systems are important in controlling electron transfer across bacterial secondary metabolite production processes which include antibiotic and pigment formation among others.
Soybean (Glycine max L. Merr.) is an important nitrogen-fixing crop that provides much of the world's protein and oil. However, the available tools for investigation of soybean gene function are ...limited. Nevertheless, chemical mutagenesis can be applied to soybean followed by screening for mutations in a target of interest using a strategy known as Targeting Induced Local Lesions IN Genomes (TILLING). We have applied TILLING to four mutagenized soybean populations, three of which were treated with ethyl methanesulfonate (EMS) and one with N-nitroso-N-methylurea (NMU).
We screened seven targets in each population and discovered a total of 116 induced mutations. The NMU-treated population and one EMS mutagenized population had similar mutation density (approximately 1/140 kb), while another EMS population had a mutation density of approximately 1/250 kb. The remaining population had a mutation density of approximately 1/550 kb. Because of soybean's polyploid history, PCR amplification of multiple targets could impede mutation discovery. Indeed, one set of primers tested in this study amplified more than a single target and produced low quality data. To address this problem, we removed an extraneous target by pretreating genomic DNA with a restriction enzyme. Digestion of the template eliminated amplification of the extraneous target and allowed the identification of four additional mutant alleles compared to untreated template.
The development of four independent populations with considerable mutation density, together with an additional method for screening closely related targets, indicates that soybean is a suitable organism for high-throughput mutation discovery even with its extensively duplicated genome.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Here we describe the utility of peptide macrocyclization through perfluoroaryl-cysteine SNAr chemistry to improve the ability of peptides to cross the blood–brain barrier. Multiple macrocyclic ...analogues of the peptide transportan-10 were investigated that displayed increased uptake in two different cell lines and improved proteolytic stability. One of these analogues (M13) exhibited substantially increased delivery across a cellular spheroid model of the blood–brain barrier. Through ex vivo imaging of mouse brains, we demonstrated that this perfluoroarene-based macrocycle of TP10 exhibits increased penetration of the brain parenchyma following intravenous administration in mice. Finally, we evaluated macrocyclic analogues of the BH3 domain of the BIM protein to assess if our approach would be applicable to a peptide of therapeutic interest. We identified a BIM BH3 analogue that showed increased penetration of the brain tissue in mice.
To evaluate a classification system to support clinical decisions for treatment of contaminated deep wounds at risk for an invasive fungal infection (IFI), we studied 246 US service members (413 ...wounds) injured in Afghanistan (2009-2014) who had laboratory evidence of fungal infection. A total of 143 wounds with persistent necrosis and laboratory evidence were classified as IFI; 120 wounds not meeting IFI criteria were classified as high suspicion (patients had localized infection signs/symptoms and had received antifungal medication for >10 days), and 150 were classified as low suspicion (failed to meet these criteria). IFI patients received more blood than other patients and had more severe injuries than patients in the low-suspicion group. Fungi of the order Mucorales were more frequently isolated from IFI (39%) and high-suspicion (21%) wounds than from low-suspicion (9%) wounds. Wounds that did not require immediate antifungal therapy lacked necrosis and localized signs/symptoms of infection and contained fungi from orders other than Mucorales.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•Pathways for Fe2+ entry into protein catalytic centers vary between ferritins.•Evidence for the transport of fully hydrated Fe2+ in vertebrate ferritins.•Near-catalytic center ...Fe2+-binding transit sites identified in vertebrate ferritins.•Roles of the strictly conserved near-catalytic center Tyr residue are revealed.
The essential metal iron presents two major problems for life: it is potentially highly toxic due to its redox activity, and its extremely low solubility in aqueous solution in the presence of O2 can make it hard to acquire and store safely. Ferritins are part of nature’s answer to these problems, as they store iron in a safe but accessible form in all types of cells. How they achieve this has been the subject of intense research for several decades. Here, we highlight recent progress in elucidating the routes by which Fe2+ ions access the catalytic ferroxidase centers, and the mechanisms by which Fe2+ is oxidized. Emerging from this is a picture of diversity, both in terms of Fe2+ entry pathways and the roles played by the structurally distinct diiron ferroxidase centers.
The synthesis of palladium oxidative addition complexes derived from unprotected peptides is described. Incorporation of 4-halophenylalanine into a peptide during solid phase peptide synthesis allows ...for subsequent oxidative addition at this position upon treatment with a palladium precursor and suitable ligand. The resulting palladium-peptide complexes are solid, storable, water-soluble, and easily purified
via
high-performance liquid chromatography. These complexes react with thiols in aqueous buffer, offering an efficient method for bioconjugation. Using this strategy, peptides can be functionalized with small molecules to prepare modified aryl thioether side-chains at low micromolar concentrations. Additionally, peptide-peptide and peptide-protein ligations are demonstrated under dilute aqueous conditions.
Peptides bearing palladium oxidative addition complexes can be synthesized from the parent aryl halide containing substrates and react with thiol functional groups of small molecules, peptides, and proteins at low micromolar concentrations.
Local and cross-border importation remain major challenges to malaria elimination and are difficult to measure using traditional surveillance data. To address this challenge, we systematically ...collected parasite genetic data and travel history from thousands of malaria cases across northeastern Namibia and estimated human mobility from mobile phone data. We observed strong fine-scale spatial structure in local parasite populations, providing positive evidence that the majority of cases were due to local transmission. This result was largely consistent with estimates from mobile phone and travel history data. However, genetic data identified more detailed and extensive evidence of parasite connectivity over hundreds of kilometers than the other data, within Namibia and across the Angolan and Zambian borders. Our results provide a framework for incorporating genetic data into malaria surveillance and provide evidence that both strengthening of local interventions and regional coordination are likely necessary to eliminate malaria in this region of Southern Africa.
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